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Biology
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Cellular and Molecular Mechanisms of Anaphylaxis: Lessons from Animal Models
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Cellular and Molecular Mechanisms of Anaphylaxis: Lessons from Animal Models

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 11113

Special Issue Editors

Prof. Dr. Abdelouahab Bellou

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Guest Editor
1. Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA
2. Institute of Sciences in Emergency Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
Interests: emergency medicine; hospital and emergency department designing; geriatric emergency medicine; critical care; physiology; immunology; shocks; quality and safety
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Paul Michel Mertès

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Guest Editor
Anaesthesia, Intensive Care and Perioperative Medicine, Nouvel Hôpital, Civil, Strasbourg University Hospital, 67000 Strasbourg, France
Interests: allergy; immunology; physiology; pharmacology; genomic; emergency medicine; animal models; anaesthesiology, critical care

Special Issue Information

Dear Colleagues,

The pathophysiological mechanisms of anaphylaxis are still under investigation. Despite intensive research produced by different groups at the international level, these mechanisms are still poorly understood. The role of pre-formed and neo-formed mediators in the onset of anaphylactic shock has been well explored, but their involvement at the cellular level remains to be clearly defined. The primum movens for the onset of anaphylaxis is an intense vasodilation responsible for the onset of shock and then respiratory and cardiac damage responsible for death with multiorgan dysfunction in very severe clinical manifestation.

Histamine is the main preformed mediator responsible for the occurrence of bronchospasm induced by bronchoconstriction leading to severe acute asthma responsible for acute respiratory failure. It is also responsible for vasodilation through stimulation of intracellular adenylate cyclase activating nitric oxide (NO) synthase leading to the production of NO, a potent vasodilator. However, our previous results do not confirm the benefit of inhibitors of NOS on anaphylactic shock published by other groups. In this Special Issue, a detailed focus on the current knowledge of the role of NO is proposed. The role of prostaglandins and leukotrienes, mediators neo-formed from the cellular membrane is suspected in the occurrence of anaphylactic shock. Our group recently showed that voltage-dependent potassium channels are probably involved in the onset of vasodilation responsible for anaphylactic shock. The role of another potent vasodilator mediator, hydrogen disulfide (H2S), remains to be demonstrated. In this Special Issue, we propose the presentation of our promising results on the inhibition of enzymes producing H2S which restores blood pressure. The mechanisms of hypovolemia linked to plasma transudation by disruption of cell junctions will also be discussed. Finally, the genomic mechanisms of the production of many mediators will be discussed in a systematic review of the literature.

Prof. Dr. Abdelouahab Bellou
Prof. Dr. Paul Michel Mertès
Guest Editors

Manuscript Submission Information

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Keywords

  • anaphylaxis
  • allergy
  • immunology
  • emergency medicine
  • animal models

Published Papers (4 papers)

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Research

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19 pages, 4897 KiB  
Article
Combined Treatment with KV Channel Inhibitor 4-Aminopyridine and either γ-Cystathionine Lyase Inhibitor β-Cyanoalanine or Epinephrine Restores Blood Pressure, and Improves Survival in the Wistar Rat Model of Anaphylactic Shock
by Abdelouahab Bellou, Nacira Sennoun, Elhadi H. Aburawi, Richard L. Jayaraj, Seth L. Alper, Ibrahim Abdallah Alfaki, Javed Yasin, Subramanian Sekar, Mohamed Shafiuallah, Suhail Al-Salam, Abderrahim Nemmar, Elsadig Kazzam, Paul Michel Mertes and Suleiman Al-Hammadi
Biology 2022, 11(10), 1455; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11101455 - 03 Oct 2022
Viewed by 1736
Abstract
The mechanism of anaphylactic shock (AS) remains incompletely understood. The potassium channel blocker 4-aminopyridine (4-AP), the inhibitors of cystathionine γ-lyase (ICSE), dl-propargylglycine (DPG) or β-cyanoalanine (BCA), and the nitric oxide (NO) synthase produce vasoconstriction and could be an alternative for the treatment of [...] Read more.
The mechanism of anaphylactic shock (AS) remains incompletely understood. The potassium channel blocker 4-aminopyridine (4-AP), the inhibitors of cystathionine γ-lyase (ICSE), dl-propargylglycine (DPG) or β-cyanoalanine (BCA), and the nitric oxide (NO) synthase produce vasoconstriction and could be an alternative for the treatment of AS. The aim of this study was to demonstrate the ability of L-NAME, ICSE alone or in combination with 4-AP to restore blood pressure (BP) and improve survival in ovalbumin (OVA) rats AS. Experimental groups included non-sensitized Wistar rats (n = 6); AS (n = 6); AS (n = 10 per group) treated i.v. with 4-AP (AS+4-AP), epinephrine (AS+EPI), AS+DPG, AS+BCA, or with L-NAME (AS+L-NAME); or AS treated with drug combinations 4-AP+DPG, 4-AP+BCA, 4-AP+L-NAME, or 4-AP+EPI. AS was induced by i.v. OVA (1 mg). Treatments were administered i.v. one minute after AS induction. Mean arterial BP (MAP), heart rate (HR), and survival were monitored for 60 min. Plasma levels of histamine, prostaglandin E2 (PGE2) and F2 (PGF2α), leukotriene B4 and C4, angiotensin II, vasopressin, oxidative stress markers, pH, HCO3, PaO2, PaCO2, and K+ were measured. OVA induced severe hypotension and all AS rats died. Moreover, 4-AP, 4-AP+EPI, or 4-AP+BCA normalized both MAP and HR and increased survival. All sensitized rats treated with 4-AP alone or with 4-AP+BCA survived. The time-integrated MAP “area under the curve” was significantly higher after combined 4-AP treatment with ICSE. Metabolic acidosis was not rescued and NO, ICSE, and Kv inhibitors differentially alter oxidative stress and plasma levels of anaphylactic mediators. The AS-induced reduction of serum angiotensin II levels was prevented by 4-AP treatment alone or in combination with other drugs. Further, 4-AP treatment combined with EPI or with BCA also increased serum PGF2α, whereas only the 4-AP+EPI combination increased serum LTB4. Serum vasopressin and angiotensin II levels were increased by 4-AP treatment alone or in combination with other drugs. Moreover, 4-AP alone and in combination with inhibition of cystathionine γ-lyase or EPI normalizes BP, increases serum vasoconstrictor levels, and improves survival in the Wistar rat model of AS. These findings suggest possible investigative treatment pathways for research into epinephrine-refractory anaphylactic shock in patients. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Anaphylaxis: Lessons from Animal Models)
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14 pages, 1622 KiB  
Article
Impaired Myocardial Mitochondrial Function in an Experimental Model of Anaphylactic Shock
by Walid Oulehri, Olivier Collange, Charles Tacquard, Abdelouahab Bellou, Julien Graff, Anne-Laure Charles, Bernard Geny and Paul-Michel Mertes
Biology 2022, 11(5), 730; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11050730 - 10 May 2022
Cited by 2 | Viewed by 1873
Abstract
Anaphylactic shock (AS) is associated with a profound vasodilation and cardiac dysfunction. The cellular mechanisms underlying AS-related cardiac dysfunction are unknown. We hypothesized that myocardial mitochondrial dysfunction may be associated with AS cardiac dysfunction. In controls and sensitized Brown Norway rats, shock was [...] Read more.
Anaphylactic shock (AS) is associated with a profound vasodilation and cardiac dysfunction. The cellular mechanisms underlying AS-related cardiac dysfunction are unknown. We hypothesized that myocardial mitochondrial dysfunction may be associated with AS cardiac dysfunction. In controls and sensitized Brown Norway rats, shock was induced by ovalbumin i.v bolus, and abdominal aortic blood flow (ABF), systemic mean arterial pressure (MAP), and lactatemia were measured for 15 min. Myocardial mitochondrial function was assessed with the evaluation of mitochondrial respiration, oxidative stress production by reactive oxygen species (ROS), reactive nitrogen species (RNS), and the measurement of superoxide dismutases (SODs) activity. Oxidative damage was assessed by lipid peroxidation. The mitochondrial ultrastructure was assessed using transmission electronic microscopy. AS was associated with a dramatic drop in ABF and MAP combined with a severe hyperlactatemia 15 min after shock induction. CI-linked substrate state (197 ± 21 vs. 144 ± 21 pmol/s/mg, p < 0.05), OXPHOS activity by complexes I and II (411 ± 47 vs. 246 ± 33 pmol/s/mg, p < 0.05), and OXPHOS activity through complex II (316 ± 40 vs. 203 ± 28 pmol/s/mg, p < 0.05) were significantly impaired. ROS and RNS production was not significantly increased, but SODs activity was significantly higher in the AS group (11.15 ± 1.02 vs. 15.50 ± 1.40 U/mL/mg protein, p = 0.02). Finally, cardiac lipid peroxidation was significantly increased in the AS group (8.50 ± 0.67 vs. 12.17 ± 1.44 µM/mg protein, p < 0.05). No obvious changes were observed in the mitochondrial ultrastructure between CON and AS groups. Our experimental model of AS results in rapid and deleterious hemodynamic effects and was associated with a myocardial mitochondrial dysfunction with oxidative damage and without mitochondrial ultrastructural injury. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Anaphylaxis: Lessons from Animal Models)
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Review

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16 pages, 591 KiB  
Review
Animal Models of IgE Anaphylaxis
by Aurélie Gouel-Chéron, Alice Dejoux, Emma Lamanna and Pierre Bruhns
Biology 2023, 12(7), 931; https://0-doi-org.brum.beds.ac.uk/10.3390/biology12070931 - 29 Jun 2023
Viewed by 2978
Abstract
Allergies and atopy have emerged as significant public health concerns, with a progressively increasing incidence over the last two decades. Anaphylaxis is the most severe form of allergic reactions, characterized by a rapid onset and potentially fatal outcome, even in healthy individuals. Due [...] Read more.
Allergies and atopy have emerged as significant public health concerns, with a progressively increasing incidence over the last two decades. Anaphylaxis is the most severe form of allergic reactions, characterized by a rapid onset and potentially fatal outcome, even in healthy individuals. Due to the unpredictable nature and potential lethality of anaphylaxis and the wide range of allergens involved, clinical studies in human patients have proven to be challenging. Diagnosis is further complicated by the lack of reliable laboratory biomarkers to confirm clinical suspicion. Thus, animal models have been developed to replicate human anaphylaxis and explore its pathophysiology. Whereas results obtained from animal models may not always be directly translatable to humans, they serve as a foundation for understanding the underlying mechanisms. Animal models are an essential tool for investigating new biomarkers that could be incorporated into the allergy workup for patients, as well as for the development of novel treatments. Two primary pathways have been described in animals and humans: classic, predominantly involving IgE and histamine, and alternative, reliant on IgG and the platelet-activating factor. This review will focus essentially on the former and aims to describe the most utilized IgE-mediated anaphylaxis animal models, including their respective advantages and limitations. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Anaphylaxis: Lessons from Animal Models)
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Other

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28 pages, 2396 KiB  
Systematic Review
Effect of Nitric Oxide Pathway Inhibition on the Evolution of Anaphylactic Shock in Animal Models: A Systematic Review
by Maryam Alfalasi, Sarah Alzaabi, Linda Östlundh, Rami H. Al-Rifai, Suhail Al-Salam, Paul Michel Mertes, Seth L. Alper, Elhadi H. Aburawi and Abdelouahab Bellou
Biology 2022, 11(6), 919; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11060919 - 16 Jun 2022
Cited by 1 | Viewed by 3460
Abstract
Nitric oxide (NO) induces vasodilation in various types of shock. The effect of pharmacological modulation of the NO pathway in anaphylactic shock (AS) remains poorly understood. Our objective was to assess, through a systematic review, whether inhibition of NO pathways (INOP) was beneficial [...] Read more.
Nitric oxide (NO) induces vasodilation in various types of shock. The effect of pharmacological modulation of the NO pathway in anaphylactic shock (AS) remains poorly understood. Our objective was to assess, through a systematic review, whether inhibition of NO pathways (INOP) was beneficial for the prevention and/or treatment of AS. A predesigned protocol for this systematic review was published in PROSPERO (CRD42019132273). A systematic literature search was conducted till March 2022 in the electronic databases PubMed, EMBASE, Scopus, Cochrane and Web of Science. Heterogeneity of the studies did not allow meta-analysis. Nine hundred ninety unique studies were identified. Of 135 studies screened in full text, 17 were included in the review. Among six inhibitors of NO pathways identified, four blocked NO synthase activity and two blocked guanylate cyclase downstream activity. Pre-treatment was used in nine studies and post-treatment in three studies. Five studies included both pre-treatment and post-treatment models. Overall, seven pre-treatment studies from fourteen showed improvement of survival and/or arterial blood pressure. Four post-treatment studies from eight showed positive outcomes. Overall, there was no strong evidence to conclude that isolated blockade of the NO/cGMP pathway is sufficient to prevent or restore anaphylactic hypotension. Further studies are needed to analyze the effect of drug combinations in the treatment of AS. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Anaphylaxis: Lessons from Animal Models)
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